Tumor Necrosis Factor (TNF)
Blockers
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Information for Healthcare Professionals: Tumor Necrosis Factor (TNF)
Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)

FDA ALERT [8/4/2009]:
FDA is requiring the manufacturers of TNF blockers to update the Boxed Warning in the
prescribing information to alert healthcare professionals of an increased risk of lymphoma and
other malignancies in children and adolescents treated with TNF blockers.

In addition to the updated Boxed Warning, FDA is requiring several other changes to the
prescribing information for TNF blockers to warn of and mitigate the risks associated with these
drugs. These changes are based on additional safety reviews and include a(n):

-Update to the Warnings section describing reported cases of leukemia in adults, adolescents,
and children. Changes to the Warnings section of the labeling will also include additional
information on malignancies in children and adolescents (see also Boxed Warning information
above).
-Update to the Adverse Events section to include information on reported cases of new-onset
psoriasis.
-Revised Medication Guide to reflect this new safety information.

This new safety information is based on FDA’s completed analysis of TNF blockers and reports of
lymphoma and other cancers in children and adolescents, a second analysis of TNF blockers and
post-marketing leukemia reports in all patients, as well as a post-marketing evaluation of new-
onset psoriasis in patients treated with these drugs.

TNF blockers are approved for the treatment of one or more of a number of immune system diseases
including juvenile idiopathic arthritis (JIA), rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s
disease, and ankylosing spondylitis.

FDA is requiring these updates to the prescribing information of TNF blockers under the authorities granted
to FDA by the Food and Drug Administration Amendments Act (FDAAA) of 2007.

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Considerations for Healthcare Professionals:

* Discuss with patients and families the increased risk of developing cancer in children and adolescents,
taking into account the clinical utility of TNF blockers, the risks/benefits of other immunosuppressive
therapies, and the risks associated with untreated illness.
* Be aware of the possibility and monitor for the emergence of malignancies during and after treatment with
TNF blockers.
* Be aware of the possibility and monitor for the emergence or worsening of psoriasis during treatment with
TNF blockers, particularly pustular and palmoplantar forms of psoriasis.
* Understand that some immune-related diseases, such as Crohn’s, have been shown to increase cancer risk
independent of treatment with TNF blockers while for others, such as juvenile idiopathic arthritis (JIA), it is
unknown whether there is an increased cancer risk.
* Inform patients, their families, and caregivers of the signs and symptoms of malignancies or psoriasis so
they are aware of and able to notify their healthcare professional of any unusual signs or symptoms.

Information for Patients

* Be aware that taking TNF blockers may increase the risk of developing lymphoma, leukemia, and other
cancers.
* Be aware that taking TNF blockers may increase the risk of developing psoriasis and may worsen pre-
existing psoriasis.
* Review the Medication Guide that accompanies TNF blockers.
* Do not stop or change medicines that have been prescribed without first talking with a knowledgeable
healthcare professional.
* Pay close attention for any signs or symptoms of cancer such as unexplained weight loss or fatigue, swollen
lymph nodes in the neck, underarms or groin, or easy bruising or bleeding.  Promptly discuss any signs and
symptoms with a healthcare professional.
* Pay close attention for any signs or symptoms of new onset psoriasis or worsening psoriasis such as red
scaly patches or raised bumps on the skin that are filled with pus.

Data Summary: Pediatric Malignancies
On June 4th 2008, FDA issued an Early Communication about an ongoing safety review of TNF blockers and
the development of lymphoma and other cancers in children and adolescents. The Early Communication was
based on approximately 30 reports of cancer in children and adolescents treated with TNF blockers. At that
time, FDA requested that manufacturers of TNF blockers approved for use in children (Enbrel, Humira, and
Remicade) submit information about all cases of cancer reported in children using these products. Cimzia,
approved in April 2008, and Simponi, approved in April 2009, were not included in FDA’s review because
they are not approved for use in children and were minimally used during the review period.

The completed FDA analysis identified 48 cases of malignancies in children and adolescents. Of the 48
cases reviewed by FDA, approximately half were lymphomas, including Hodgkin’s and non-Hodgkin’s
lymphoma. Other malignancies reported include leukemia, melanoma, and solid organ cancers. Malignancies
such as leiomyosarcoma, hepatic malignancies, and renal cell carcinoma, which are rare in children, were
also reported. Of the 48 cases of malignancy, there were 11 deaths.  The causes of death included
hepatosplenic T-cell lymphoma (9 cases) and T-cell lymphoma (1 case). In the remaining case, the patient
died from sepsis after achieving remission of the lymphoma.

The FDA analysis showed that U.S. reporting rates for cases of malignancy with Remicade (infliximab) were
consistently higher compared to expected background rates for lymphomas and all malignancies. The
malignancy reporting rates for Enbrel (etancercept) were also higher than background rates for lymphomas,
but were similar to background rates for all malignancies. The malignancy reporting rates for Humira
(adalimumab) and Cimzia (certolizumab pegol) were not calculated during the analysis because of minimal
use in pediatric patients. Simponi (golimumab) was not approved at the time of the analysis and therefore
was not included. The observed reporting rates offer very limited inference into the potential differences in
malignancy risk among the TNF blockers because of uncertainties about actual patient exposure to treatment
and the possibility of underreporting of malignancy cases.

The majority of the 48 patients (88%) were also using other immunosuppressive medications such as
azathioprine and methotrexate, which currently have warnings of increased risk of lymphoma in their
prescribing information. Although there were other contributory factors, the role of TNF blockers in the
development of malignancies in children and adolescents could not be excluded.

Therefore, FDA concludes there is an increased risk of malignancy with TNF blockers. However, due to the
relatively rare occurrence of these cancers, the limited number of pediatric patients treated with TNF
blockers, and the possible role of other immunosuppressive therapies used concomitantly with TNF blockers,
FDA is unable at this time to fully characterize the strength of the association between using TNF blockers
and developing a malignancy.  Additional data are expected from the ongoing long term, observational, post-
marketing studies and registries that are being conducted by the TNF blocker manufacturers.  In addition,
FDA is working with TNF blocker manufacturers to explore new ways to further define the risk of malignancy
in children and adolescents using TNF blockers.

Data Summary: Leukemia
FDA reviewed 147 post-marketing reports of leukemia in all patients, including adults, using TNF blockers. Of
the 147 cases, acute myeloid leukemia (44 cases), chronic lymphocytic leukemia (31 cases), and chronic
myeloid leukemia (23 cases) were the most frequently classified types of leukemia reported. Four pediatric
cases of leukemia were reported in the review. Most patients (61%) were also receiving other
immunosuppressive therapies. There were a total of 30 deaths reported. In 26 of the 30 deaths, the cause
was reported to be leukemia, and the event was associated with the use of TNF blockers.  The average time
to onset of leukemia was within the first 1 to 2 years of therapy.

The interpretation of these findings is complicated by the fact that published epidemiological studies suggest
that patients with rheumatoid arthritis may be at increased risk of leukemia, independent of any treatment
with TNF blockers. However, based on the available data, FDA concludes there is a possible association
between treatment with TNF blockers and the development of leukemia in all patients treated with these
drugs. The current prescribing information for TNF blockers contains a warning for malignancies, but does
not specifically mention leukemia. Therefore, to alert healthcare professionals to this possible association,
FDA is requiring the incorporation of information on post-marketing reports of leukemia into the prescribing
information for TNF blockers.

Data Summary: Psoriasis
In a separate analysis, FDA reviewed 69 cases of new onset psoriasis, including pustular (17 cases) and
palmoplantar (15 cases), in all patients using TNF blockers for treatment of autoimmune and rheumatic
conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, there were 2 pediatric reports of new
onset psoriasis. The development of psoriasis during treatment with TNF blockers occurred with varying
duration from weeks to years after drug initiation. Twelve of the psoriasis cases resulted in hospitalization,
which was the most severe outcome reported. The majority of patients experienced improvements of their
psoriasis following discontinuation of the TNF blocker. None of the cases reported pre-existing psoriasis prior
to the initiation of TNF blocker therapy.

Due to the number of reported cases and the temporal relationship between the initiation of TNF blockers
and development of psoriasis, FDA concludes there is a possible association between the development of
psoriasis and use of these drugs. Therefore, FDA is requiring an update to the Adverse Events section of the
prescribing information to inform healthcare professionals about reported cases of new-onset psoriasis
associated with the use of TNF blockers.